Mutations in N-cadherin and a Stardust homolog, Nagie oko, affect cell-cycle exit in zebrafish retina

Abstract

It has been reported that the loss of apicobasal cell polarity and the disruption of adherens junctions induce hyperplasia in the mouse developing brain. However, it is not fully understood whether hyperplasia is caused by an enhanced cell proliferation, an inhibited neurogenesis, or both. In this study, we found that the ratio of the number of proliferating progenitor cells to the total number of retinal cells increases in the neurogenic stages in zebrafish n-cadherin (ncad) and nagie oko (nok) mutants, in which the apicobasal cell polarity and adherens junctions in the retinal epithelium are disrupted. The cell-cycle progression was not altered in the ncad and nok mutants. Rather, the ratio of the number of cells undergoing neurogenic cell division to the total number of cells undergoing mitosis decreased in the ncad and nok mutant retinas, suggesting that the switching from proliferative cell division to neurogenic cell division was compromised in these mutant retinas. These findings suggest that the inhibition of neurogenesis is a primary defect that causes hyperplasia in the ncad and nok mutant retinas. The Hedgehog-protein kinase A signaling pathway and the Notch signaling pathway regulate retinal neurogenesis in zebrafish. We found that both signaling pathways are involved in the generation of neurogenic defects in the ncad and nok mutant retinas. Taken together, these findings suggest that apicobasal cell polarity and epithelial integrity are essential for retinal neurogenesis in zebrafish.

ArhGEF18 regulates RhoA-Rock2 signaling to maintain neuro-epithelial apico-basal polarity and proliferation

“…Cell cycle exit of med mutant RPCs is decreased and, as a consequence, the relative number of proliferating RPCs is severely increased. In addition, mutations in Ncadherin and Pals1 result in decreased neurogenic divisions of RPCs in the zebrafish retina, suggesting that apico-basal polarity regulates the balance between proliferative and neurogenic divisions (Yamaguchi et al, 2010). It has been hypothesized that segregation of cellular determinants and nuclear position along the a-b axis during cell divisions are crucial for this process.…”

“…Consistent with the location of ectopic BrdU-positive nuclei, these ectopic pH3-positive RPCs were mostly in the central region of the retina at 3-5 dpf (supplementary material Fig S1A,B and data not shown). Furthermore, analysis of cell cycle exit at stage 27 (2.8 dpf) using ath5 as a marker for neurogenic divisions (Del Bene et al, 2007;Yamaguchi et al, 2010) provided further evidence that cell cycle exit is significantly reduced in med mutant retinae (supplementary material Fig. S1J-L).…”

Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis

“…For example, in dynactin1a mutants, the depth of nuclear migration is augmented and the retinal neuroepithelia show a higher proportion of neurogenic divisions. The relationship between nuclear position and neurogenesis depends on apicobasal cell polarity (Baye and Link, 2007), and mutations in a variety of genes essential for apicobasal cell polarity affect neurogenesis (Yamaguchi et al, 2010). The role of IKNM on neurogenesis is important in structures other than zebrafish retina, as experimental manipulations that alter IKNM in mouse cortical neuroepithelia affect cell cycle exit and generation of neurons (Ge et al, 2010;Schenk et al, 2009;Tsai et al, 2005;Xie et al, 2007;Zhang et al, 2009).…”

Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

“…Besides interfering with angiogenic blood vessels formation, the compounds from valproylglycine hydrazide series also induced severe cardiac edema (Figure 1 black arrow in D). The cardiac edema has also been shown in previous studies which are HDAC mutant (Pillai et al, 2004;Yamaguchi et al, 2005) or embryos were treated with VPA or any other HDAC inhibitor (Farooq et al, 2008;Cao et al, 2009;Johnson et al, 2013). We have not analyzed the HDAC enzymatic activity with these compounds but most likely that the cardiac edema which is result of newly synthesized VPA derivatives could be due to their HDAC inhibition activity.…”